Neurotransmitter transporters (NT-S) have fundamental importance for many physiological processes of neurotransmission, and especially in the mechanisms of drug addiction and abuse. The NT-s to be studied in this Program Project Grant (PPG) are the transporters for dopamine (DT), serotonin (SERT), norepinephrine (NET), and GABA (GAT). Together, they are major molecular targets responsible. for rewarding properties and abuse potential of the most widely used illicit drugs (e.g., cocaine and amphetamine derivatives such as MDMA), and they also play a central role in mechanisms of depression and anxiety. This motivates the multi- disciplinary PPG proposal which addresses in the combined and coordinated approach of six component Projects, the functional richness of the NT-s, their structural underpinnings, and the structure-activity (S-A) basis for the variety of effects elicited by substrates and ligands. The approaches rest on a molecular perspective and a structural context that are only now emerging slowly for NT-s. A synergistic construct of the research plan of the PPG ensures that findings and inferences about structure and function emerging from the study of one NT system in one of the Projects will be directly compared and tested in another. This is stimulated and facilitated by the sharing structural context provided by the molecular models from Project 1. Functional probing with electrophysiological, pharmacological and biochemical methods in Projects 2-6, aims to explore the dynamics mechanisms of the systems. The related structural probing of the NT-s and complexes with ligands will link experimental approaches (including chemical modification, the 3,4,6 with comprehensive computational modeling, structure analysis and prediction, and dynamics simulation in Project 1. Special attention to ligand S-A considerations will be given in Projects 1 and 2, and the results will guide choices of ligands and systems in the other Projects. The combined focus of the PPG is to organize the insights from experiment and computation into a mechanistic understanding of the relation between the molecular architecture of NT-s, and their biological functions. This will be supported by inter-Project collaborations, shared Core activities, and new shared resources. The expected insights concerning the considerations of novel pharmacological interventions for treatment and prevention of psychostimulant abuse.